摘要
目的：内源性硫化氢(Hydrogen Sulfide,H2S)作为一个新的神经调质,参与了中枢神经系统的生理功能的调节和疾病过程。本课题的目的是探讨中枢神经系统内源性H2S对正常大鼠血流动力学的调节作用及其机制。
方法：侧脑室给予外源性H2S饱和溶液和H2S生成酶胱硫醚-p-合成酶(cystathionine β-synthase, CBS)或3-巯基丙酮酸(3-mercaptopyruvate, MP)或H2S前体半胱氨酸氨或胱硫醚-p-合成酶抑制剂羟胺(Hydroxylamine,HA)及不同的干预试剂；采用左心室和股动脉插管法及四道生理记录仪记录平均动脉血压(mean arterial pressure,MABP)、心率(heart rate,HR)、左室收缩压(Left ventricle systolic pressure,LVSP)、左室舒张末压(left ventricle end-diastolic pressure,LVEDP)及左室最大压力上升及下降心室内压的变化率(rate of the rise of LV ventricular pressure,±p/dt);采用气管插管法测呼吸深度和呼吸频率；采用免疫印迹法检测3-巯基丙酮酸硫基转移酶和胱硫醚-p-合成酶蛋白浓度；采用亚甲基蓝法测定组织硫化氢表达水平；采用生物化学方法测定心肌和血管组织Na+-K+-ATPase活性；采用放射免疫法测定血浆洋地黄含量。
结果：(1)免疫印迹实验证实,中枢神经系统存在高水平的H2S生成酶CBS和MPST。CBS依赖的H2S生成前体半胱氨酸,下丘脑和皮质分别生成62.5±5.3和63.8±10.3nmol/min/g组织的H2S。给予3-巯基丙酮酸,H2S生成大约是给予半胱氨酸的2倍即125.7±16.8和134.6±17.7nmol/min/g组织,各自与半胱氨酸生成H2S比较,两者的差异有显著意义(a11P<0.01)。而预先给予CBS的抑制剂羟胺(HA),再给予半胱氨酸和MPST, HA能够显著抑制半胱氨酸生成H2S,但不影响MPST生成H2S的作用。
(2)侧脑室(ICV)给予不同浓度H2S饱和缓冲液可剂量依赖性的导致大鼠平均动脉血压急剧下降,而后迅速上升。其最大降低幅度分别是7.8±2.3、11.4±2.6和16.1±3.6mmHg,最大上升幅度分别是9.2±3.4、12.2±2.1和20.8±2.5mmHg,各组变化最显著的对应时间点统计学均有显著差异(p<0.001)。
(3)ICV连续缓慢注射H2S饱和缓冲液大鼠平均动脉血压先降低迅速升高而后缓慢升高,在110min时达到最高值即38±8.6mmHg,峰值出现在100-110min之间,观察期内血压没有下降。与对照组比较,各时间点差异均有统计学意义(P<0.01),而心率和呼吸没有显著的变化。
(4)ICV分别注射H2S生成前体L-半胱氨酸(L-Cys)、H2S生成酶3-巯基丙酮酸硫基转移酶(MPST)导致快速的升高平均动脉血压。ICV注射H2S生成酶胱硫醚-β-合成酶抑制剂羟胺(HA),平均动脉血压快速下降而后缓慢的回升。
(5)ICV注射L-Cys在观察期内心率缓慢的降低,其最大降低值大约是100次/分,与正常对照比较统计学有显著差异(P<0.01)；ICV注射HA或注射H2S气体饱和缓冲液(2.8μmol/kg)对心率没有影响；预先ICV给予HA阻断CBS活性,10min后再ICV注射L-Cys,显著的减弱L-Cys减慢心率的作用(P<0.01)。
(6)ICV微量注射泵持续注射不同浓度的H2S饱和溶液,剂量依赖性的增加左心室发展压和心室发展压最大变化率,但对左心室舒张末压没有显著影响；ICV注射H2S生成前体L-Cys增加左心室发展压和心室发展压变化率；相反,H2S生成酶CBS抑制剂羟胺能够短暂的降低左心室发展压和心室发展压最大变化率。
(7)外周静脉给与α受体阻断剂酚妥拉明,几乎完全阻断了中枢给予外源性H2S和内源性H2S的升压效应,与对照组比较统计学有显著差异(P<0.01)。
(8)ICV不同浓度的H2S饱和缓冲液可剂量依赖性的显著增加大鼠的呼吸深度减慢呼吸频率,在前1分钟内变化最显著,而后呼吸逐渐恢复正常,各组间均有统计学意义(P均<0.001)。
(9)ICV给予H2S饱和缓冲液和KATP通道开放剂吡那地尔,能够显著的降低平均动脉血压。而预先给与KATP通道阻滞剂glibenclimad,能够显著的阻断H2S饱和缓冲液和KATP通道开放剂吡那地尔的降压效应(P<0.01),但不影响H2S的升压效应。
(10)β受体阻断剂美托洛尔显著的抑制了中枢内源性H2S对心脏的正性肌力作用,而glibenclamide却没有影响。
(11)与生理盐水组比较,I.C.V半胱氨酸组血浆内洋地黄类因子水平增加了大约1倍(P<0.01)。而羟胺(HA)轻微的降低了洋地黄类因子水平,与生理盐水组比较没有显著差异(P>0.05)。
(12)与对照组比较,内源性H2S显著抑制了心脏和腹主动脉检测心肌和腹主动脉Na+-K+-ATP酶活性(P<0.001)；而羟胺显著增加了它们的Na+-K+-ATP酶活性(P<0.001)
结论：中枢神经系统由CBS和MPST催化产生高水平的内源性H2S。中枢给予外源性和内源性H2S均能够增加大鼠平均动脉血压,减慢心率,增强心功能。中枢神经系统H2S通过激活外周交感神经活性、增加呼吸深度减慢呼吸频率、激活中枢KATP通道、而调节动脉血压；通过激活外周交感神经活性、增加心肌内源性洋地黄类因子的释放和抑制心肌和腹主动脉Na-K+-ATP酶活性增强心功能。
AIM:Endogenous hydrogen sulfide is recongnized as a new neuromodulator which take part in the regulation of central neurous system phyisology and diseases. To explore the effect of endogenous hydrogen sulfide on hemodynamic effects and its probable mechanism.
Method:Rats were given H2S gas saturation buffer and H2S different precursor-L-Cys or MP or CBS inhibitor-HA and different intervention agent by lateral cerebral ventricle(I.C.V.);the mean arterial pressure (MAP) and heart rate (HR) were recorded by Powerlab/4S instruments. To measure left ventricular pressure, the arterial catheters were inserted into the left-ventricle by right carotid arteries, and the left ventricular developed pressure (LVDP), left-ventricle maximal rate of systolic and diastolic pressure development (±LVdp/dtmax) were recorded; respiration were monitored by tracheal intubation. Western blot for MPST and CBS protein concentration; Measurement of H2S production by methylene; Measurement of the Na+-K+-ATPase activity by biological chemistry; Radioimmunoassay for endogenous digitalis like factors。
Result:(1) Western blotting data showed, that both CBS and MPST protein expressed in thalamus and cortex; using L-cys as precursor (CBS dependent), the H2S releasing from thalamus and cortex were62.5±5.3and63.8±10.3nmol/min/g tissues; while administrated MP as precursor (MPST dependent), the endogenous H2S generation were approximate to two-fold (125.7±16.8,134.6±17.7nmol/min/g tissues respectively; all P<0.01) in the thalamus and cortex, comparison to L-cys as precursor. Pre-incubated with HA-an inhibitor of CBS, significantly blocked the endogenous H2S production from L-Cys; but not affected H2S production form MP。
(2) The exogenous H2S injection by I.C.V. induced a dose-dependent transient hypotension (within in10-240seconds), the time of hypotensive effect was longer in low concentration H2S. After transient hypotension, dramatic MAP increased rapidly in dose-dependent manner were observed and maintained long times (5-20min).
(3) Continuously injected H2S gradually increased MAP during2hours. At the end of injection, the MAP increased about30mmHg compared with physiological saline injection, peaked between90min and100min of infusion (P<0.01versus baseline).
(4) Bonus injection L-Cys, induced quickly dramatic elevation of MAP, the peak appeared at10-20min, the maximum changes of MAP was about43mmHg and the pulse pressure also increased approximately to1fold. As following, the MAP and pulse pressure recovered gradually. Bonus injection MP, the MAP slowly gradually increased, the maximum changes of MAP was approximate to24mmHg, which continued to60min (the end of observation) without attenuation. Administration with CBS inhibitor-HA block endogenous H2S, lowered the MAP for20min, the maximum reduction of MAP was about20mmHg.
(5) I.C.V. administrated the L-Cys induced the heart rate decreased during60min by bonus injection L-Cys, the maximum changes of heart rate was approximate to100bpm (P<0.01versus baseline). Injection HA or intravenous injection H2S did not affect heart rate. Pretreartment with HA blocked CBS activity significantly attenuated the heart rate inhibition by L-Cys (P<0.01). Whereas pre-intravenous injection phentolamine did not affect (p>0.05). Pretreatment with HA inhibition CBS activity in part blocked the effects of L-Cys, The phentolamine also partly blocked the hypertensive effect of L-Cys.
(6) Continuously injected different concentration of H2S by I.C.V. and found that increasing CNS endogenous H2S production induced dose-dependently increases left ventricular develop-pressure (LVDP) and±LVdp/dtmax, without affecting left ventricular end of diastolic pressure. Bonus injection H2S precursor L-Cys also increased LVDP and±LVdp/dtmax; on the contrary, HA injection induced a transient decreases of LVDP and±LVdp/dtmax.
(7) Intravenous injection phenolamine alpha receptor blocker largely blocked the hypertensive effects of H2S (P<0.01).
(8)The I.C.V.injection H2S induced a dose-dependent deeper and slower respiration.
(9) Pre-injection KATP channel blocker-glibenclamide by I.C.V), significantly blocked the transient hypotension effects of H2S (P<0.01); whereas did not block the following hypertension effects;
(10) The beta receptor blocker metoprolol in part lowered the positive inotropic effect of L-Cys, but not glibenclamide (P<0.05).
(11) L-Cys I.C.V. quickly elevated the plasma EDLF level approximately to1fold compared with physiological saline injection control group (P<0.01). HA injection slightly lowered the EDLF level in plasma but no statistical difference.
(12) The L-Cys I.C.V. inhibited cardiac and aortic membrane Na+-K+-ATPase, otherwise, HA increased it.
Conclusion:Central nervous system endogenous hydrogen sulfide up-regulated mean arterial pressure and cardiac systolic function by activation sympathetic nervous, increase the depth of respiration to slow down the respiratory rate, the activation of central KATP channels, inhibition of the cardiac and abdominal aortic micro-vesicles the Na+-K+-ATPase activity and increase endogenous digitalis like factorrelease.
引文
[1]Qu K, Lee SW, Bian JS, Low CM, Wong PT. Hydrogen sulfide:neurochemistry and neurobiology[J]. Neurochem Int.2008;52:155-165.
[2]Lin CH, Mao IF, Tsai PH, Chuang HY, Chen YJ, Chen ML. Sulfur-rich geothermal emissions elevate acid aerosol levels in metropolitan Taipei[J]. Environ Res. 2010;l 10:536-543.
[3]Kilburn KH, Thrasher JD, Gray MR. Low-level hydrogen sulfide and central nervous system dysfunction[J]. Toxicol Ind Health.2010;26:387-405.
[4]Kimura H. Hydrogen sulfide:Its production, release and functions[J]. Amino Acids. 2011;41:113-121
[5]Dhaese I, Van Colen I, Lefebvre RA. Mechanisms of action of hydrogen sulfide in relaxation of mouse distal colonic smooth muscle[J]. Eur J Pharmacol.2010; 628:179-186.
[6]Shibuya N, Tanaka M, Yoshida M, Ogasawara Y, Togawa T, Ishii K, Kimura H. 3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain[J]. Antioxid Redox Signal.2009;11:703-714.
[7]Lu M, Choo CH, Hu LF, Tan BH, Hu G, Bian JS. Hydrogen sulfide regulates intracellular pH in rat primary cultured glia cells[J]. Neurosci Res.2010; 66:92-98.
[8]Grossi L. Hydrogen sulfide induces nitric oxide release from nitrite[J]. Bioorg Med Chem Lett.2009; 19:6092-6094.
[9]Hughes MN, Centelles MN, Moore KP. Making and working with hydrogen sulfide: The chemistry and generation of hydrogen sulfide in vitro and its measurement in vivo: a review[J]. Free Radic Biol Med.2009;47:1346-1353.
[10]Pae HO, Lee YC, Jo EK, Chung HT. Subtle interplay of endogenous bioactive gases (NO, CO and H(2)S) in inflammation[J]. Arch Pharm Res.2009; 32:1155-1162.
[11]Minamishima S, Bougaki M, Sips PY, Yu JD, Minamishima YA, Elrod JW, Lefer DJ, Bloch KD, Ichinose F. Hydrogen sulfide improves survival after cardiac arrest and cardiopulmonary resuscitation via a nitric oxide synthase 3-dependent mechanism in mice[J]. Circulation.2009; 120:888-896.
[12]Lu M, Hu LF, Hu G, Bian JS. Hydrogen sulfide protects astrocytes against H(2)O(2)-induced neural injury via enhancing glutamate uptake[J]. Free Radic Biol Med.2008;45(12):1705-1713.
[13]Whiteman M, Cheung NS, Zhu YZ, Chu SH, Siau JL, Wong BS, Armstrong JS, Moore PK. Hydrogen sulphide:a novel inhibitor of hypochlorous acid-mediated oxidative damage in the brain[J]?Biochem Biophys Res Commun.2005;326(4):794-798.
[14]Liu YY, Sparatore A, Del Soldato P, Bian JS. H2S releasing aspirin protects amyloid beta induced cell toxicity in BV-2 microglial cells[J]. Neuroscience. 2011;193:80-88.
[15]Liang GH, Adebiyi A, Leo MD, McNally EM, Leffler CW, Jaggar JH. Hydrogen sulfide dilates cerebral arterioles by activating smooth muscle cell plasma membrane KATp channels[J]. Am J Physiol Heart Circ Physiol.2011;300(6):H2088-2095.
[16]Guo Q, Jin S, Wang XL, Wang R, Xiao L, He RR, Wu YM. Hydrogen sulfide in the rostral ventrolateral medulla inhibits sympathetic vasomotor tone through ATP-sensitive K+channels[J]. J Pharmacol Exp Ther.2011;338(2):458-465.
[17]Rosenegger D, Roth S, Lukowiak K. Learning and memory in Lymnaea are negatively altered by acute low-level concentrations of hydrogen sulphide[J].J Exp Biol. 2004;207(Pt 15):2621-2630.
[18]Ufnal M, Sikora M, Dudek M. Exogenous hydrogen sulfide produces hemodynamic effects by triggering central neuroregulatory mechanisms[J]. Acta Neurobiol Exp (Wars).2008; 68:382-388.
[19]Dawe GS, Han SP, Bian JS, Moore PK. Hydrogen sulphide in the hypothalamus causes an ATP-sensitive K+ channel-dependent decrease in blood pressure in freely moving rats[J]. Neuroscience.2008;152:169-177.
[20]Ren YS, Yang JH, Zhang J, Pan CS, Yang J, Zhao J,Pang YZ, Tang CS, Qi YF. IntermedinI-53 in central nervous system elevates arterial blood pressure in rat[J].Peptides.2006;27:74-79.
[21]Roh J, Chang CL, Bhalla A, Klein C, Hsu SY. Intermedin is a calcitonin/calcitonin gene-related peptide family peptide acting through the calcitonin receptor-like receptor/receptor activity-modifying protein receptor complexes[J]. J Biol Chem.2004;279(8):7264-7274.
[22]Pan CS, Yang JH, Cai DY, Zhao J, Gerns H, Yang J, Chang JK, Tang CS, Qi YF. Cardiovascular effects of newly discovered peptide intermedin/adrenomedullin 2[J]. Peptides.2005;26:1640-1646
[23]Pan CS, Jiang W, Zhong GZ, Zhao J, Pang YZ, Tang CS, Qi YF.Hypertension induced by nitric oxide synthase inhibitor increases responsiveness of ventricular myocardium and aorta of rat tissue to adrenomedullin stimulation in vitro[J].Life Sci. 2005;78(4):398-405.
[24]StipanukMH, Beck PW. Characterization of the enzymic capacity for cysteine desulphhydration in liver and kidney of the rat[J]. Biochem J.1982,206:267-277
[25]Chang L, Geng B, Yu F, Zhao J, Jiang H, Du J, Tang C.Hydrogen sulfide inhibits myocardial injury induced by homocysteine in rats[J]. Amino Acids. 2008;34(4):573-85.
[26]Jones LR. Rapid preparation of canine cardiac sarcolemmal vesicles by sucrose flotation[J].Methods Enzymol.1988; 157:85-91.
[27]D'Urso G, Frascarelli S, Balzan S, Zucchi R, Montali U.Production of ouabain-like factor in normal and ischemic rat heart[J].J Cardiovasc Pharmacol.2004;43(5):657-62.
[28]Balzan S, Montali U, Di Bartolo V, Ghione S.Further evidence for an endogenous digitalis-like compound in newborn and adult plasma detected by anti-ouabain antiserum[J].Life Sci.1997;60(12):893-8.
[29]Hu LF, Lu M, Hon Wong PT, Bian JS. Hydrogen sulfide:Neurophysiology and neuropathology[J]. Antioxid Redox Signal.2011; 15(2):405-19
[30]Nagahara N, Ito T, Kitamura H, Nishino T. Tissue and subcellular distribution of mercaptopyruvate sulfurtransferase in the rat:Confocal laser fluorescence and immunoelectron microscopic studies combined with biochemical analysis[J]. Histochem Cell Biol.1998;110:243-250.
[31]Xiao L, Wu YM, Zhang H, Liu YX, He RR.Hydrogen sulfide facilitates carotid sinus baroreflex in anesthetized rats[J]. Acta Pharmacol Sin.2006;27:294-298.
[32]de Wardener HE and Clarkson EM. Concept of natriuretic hormone[J]. Physiol Rev. 1985;65:658-759.
[33]Goto A, Yamada K, Yagi N, Yoshioka M, and Sugimoto T. Physiology and pharmacology of endogenous digitalis-like factors[J]. Pharmacol Rev 1992. 44:377-399.
[34]Schoner W. Endogenous digitalis-like factors[J]. Clin Exp Hypertens A. 1992;14:767-814.
[35]Bagrov AY, Shapiro JI, Fedorova OV. Endogenous cardiotonic steroids:physiology, pharmacology, and novel therapeutic targets[J]. Pharmacol Rev.2009;61:9-38.
[36]Dello Russo C, Tringali G, Ragazzoni E, Maggiano N, Menini E, Vairano M, Preziosi P, Navarra P. Evidence that hydrogen sulphide can modulate hypothalamo-pituitary-adrenal axis function:In vitro and in vivo studies in the rat[J]. J Neuroendocrinol.2000; 12:225-233
[1]Kimura H. Hydrogen sulfide:its production, release and functions.Amino Acids[J]. Nihon Yakurigaku Zasshi.2012;139(1):6-8.
[2]Olson KR, Whitfield NL, Bearden SE, St LJ, Nilson E, Gao Y,Madden JA. Hypoxic pulmonary vasodilation:A paradigm shift with a hydrogen sulfide mechanism[J]. Am J Physiol Regul Integr Comp Physiol.2010;298:R51-R60
[3]Kabil O, Banerjee R. Redox biochemistry of hydrogen sulfide[J]. J Biol Chem,2010. 285:21903-21907.
[4]Ishigami M, Hiraki K, Umemura K, Ogasawara Y, Ishii K, Kimura H. A source of hydrogen sulfide and a mechanism of its release in the brain[J]. Antioxid Redox Signal 2009; 11:205-214
[5]Shibuya N, Tanaka M, Yoshida M, Ogasawara Y, Togawa T, Ishii K,Kimura H. 3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain[J]. Antioxid Redox Signal.2009; 11:703-714,
[6]Bearden SE, Beard RS Jr, Pfau JC. Extracellular transsulfuration generates hydrogen sulfide from homocysteine and protects endothelium from redox stress[J]. Am J Physiol Heart Circ Physiol,2010;299:H1568-H1576,
[7]Baumgart K, Wagner F, Groger M, Weber S, Barth E, Vogt JA,Wachter U, Huber-Lang M, Knoferl MW, Albuszies G, Georgieff M,Asfar P, Szabo C, Calzia E, Radermacher P, Simkova V. Cardiac and metabolic effects of hypothermia and inhaled hydrogen sulfide in anesthetized and ventilated mice[J]. Crit Care Med,2010;38: 588-595.
[8]Stipanuk MH. Sulfur amino acid metabolism:pathways for production and removal of homocysteine and cysteine[J]. Annu Rev Nutr,2004;24:539-577.
[9]Banerjee R, Zou CG. Redox regulation and reaction mechanism of human cystathionine-beta-synthase:a PLP-dependent hemesensor protein[J]. Arch Biochem Biophys,2005;433:144-156.
[10]Dominy JE, Stipanuk MH. New roles for cysteine and transsulfuration enzymes: production of H2S, a neuromodulator and smooth muscle relaxant[J]. Nutr Rev,2004; 62:348-353.
[11]Kabil O, Banerjee R. Redox biochemistry of hydrogen sulfide[J]. J Biol Chem, 2010;285:21903-21907.
[12]Singh S, Padovani D, Leslie RA, Chiku T, Banerjee R. Relative contributions of cystathionine beta-synthase and gamma-cystathionase to H2S biogenesis via alternative trans-sulfuration reactions[J]. J Biol Chem,2009;284:22457-22466
[13]Szabo C. Hydrogen sulphide and its therapeutic potential[J]. Nat Rev Drug Discov. 2007;6:917-935
[14]Hildebrandt TM, Grieshaber MK. Three enzymatic activities catalyze the oxidation of sulfide to thiosulfate in mammalian and invertebrate mitochondria[J].2008;FEBS J 275:3352-3361.
[15]Lagoutte E, Mimoun S, Andriamihaja M, Chaumontet C, Blachier F, Bouillaud F. Oxidation of hydrogen sulfide remains a priority in mammalian cells and causes reverse electron transfer in colonocytes[J]. Biochim Biophys Acta, 2010; 1797:1500-1511.
[16]Abe K and Kimura H. The possible role of hydrogen sulfide as an endogenous neuromodulator[J].J Neurosci.1996; 16(3):1066-1071.
[17]Enokido Y, Suzuki E, Iwasawa K, Namekata K, Okazawa H, Kimura H.Cystathionine beta-synthase, a key enzyme for homocysteine metabolism, is preferentially expressed in the radial glia/astrocyte lineage of developing mouse CNS[J]. FASEB J.2005;19(13):1854-1856.
[18]Ichinohe A, Kanaumi T, Takashima S, Enokido Y, Nagai Y, Kimura H.Cystathionine beta-synthase is enriched in the brains of Down's patients[J]. Biochem. Biophys. Res. Commun.2005;338(3):338,1547-1550.
[19]Hu LF, Wong PT, Moore PK, Bian JS.Hydrogen sulfide attenuates lipopolysaccharide-induced inflammation by inhibition of p38 mitogen-activated protein kinase in microglia[J]. J Neurochem.2007;100(4):1121-1128.
[20]Lee SW, Hu YS, Hu LF, Lu Q, Dawe GS, Moore PK, Wong PT, Bian JS.Hydrogen sulphide regulates calcium homeostasis in microglial cells[J].Glia.2006;54(2):116-124.
[21]Distrutti E, Sediari L, Mencarelli A, Renga B, Orlandi S, Antonelli E, Roviezzo F, Morelli A, Cirino G, Wallace JL, Fiorucci S.Evidence that hydrogen sulfide exerts antinociceptive effects in the gastrointestinal tract by activating KATP channels[J]. J. Pharmacol. J Pharmacol Exp Ther.2006;316(1):325-335.
[22]Garcia-Bereguiain MA, Samhan-Arias AK., Martin-Romero F J,Gutierrez-Merino C. Hydrogen sulfide raises cytosolic calcium in neurons through activation of L-type Ca2+ channels[J]. Antioxid. Antioxid Redox Signal.2008;10(1):31-42.
[23]Shibuya N, Tanaka M, Yoshida M, Ogasawara Y, Togawa T, Ishii K, Kimura H, 3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain[J]. Antioxid. Redox Signal.2009; 11:703-709.
[24]Lee M, Tazzari V, Giustarini D, Rossi R, Sparatore A, Del Soldato P, McGeer E, McGeer PL.Effects of hydrogen sulfide-releasing L-DOPA derivatives on glial activation:potential for treating Parkinson disease[J].J Biol Chem. 2010;285(23):17318-17328.
[25]Shibuya N, Tanaka M, Yoshida M, Ogasawara Y, Togawa T, Ishii K, Kimura H. 3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain[J]. Antioxid Redox Signal 2009.11:703-714.
[26]Lu M, Choo CH, Hu LF, Tan BH, Hu G, Bian JS. Hydrogen sulfide regulates intracellular pH in rat primary cultured glia cells[J]. Neurosci Res 2010.66:92-98.
[27]Kimura H.Hydrogen Sulfide Induces Cyclic AMP and Modulates the NMDA Receptor[J]. Biochemical and Biophysical Research Communications,2000; 267, 129-133.
[28]Grossi L. Hydrogen sulfide induces nitric oxide release from nitrite[J]. Bioorg Med Chem Lett 2009.19:6092-6094.
[29]Han Y, Qin J, Chang X, Yang Z, Bu D, Du J. Modulating effect of hydrogen sulfide on gamma-aminobutyric acid B receptor in recurrent febrile seizures in rats[J]. Neurosci Res.2005;53(2):216-219.
[30]Lu M, Hu LF, Hu G, Bian JS. Hydrogen sulfide protects astrocytes against H(2)O(2)-induced neural injury via enhancing glutamate uptake[J]. Free Radic Biol Med.2008;45(12):1705-1713.
[31]Whiteman M, Cheung NS, Zhu YZ, Chu SH, Siau JL, Wong BS, Armstrong JS, Moore PK. Hydrogen sulphide:a novel inhibitor of hypochlorous acid-mediated oxidative damage in the brain[J]?Biochem Biophys Res Commun.2005;326(4):794-798.
[32]Liu YY, Sparatore A, Del Soldato P, Bian JS.H2S releasing aspirin protects amyloid beta induced cell toxicity in BV-2 microglial cells[J]. Neuroscience. 2011;193:80-88.
[33]Lee SW, Hu YS, Hu LF, Lu Q, Dawe GS, Moore PK., Wong PT, Bian JS. Hydrogen sulphide regulates calcium homeostasis in microglial cells[J].2006;Glia 54,116-110.
[34]Nagai Y, Tsugane M, Oka J, Kimura H. Hydrogen sulfide induces calcium waves in astrocytes[J]. FASEB J.2004;18,557-561.
[35]Liang GH, Adebiyi A, Leo MD, McNally EM, Leffler CW, Jaggar JH. Hydrogen sulfide dilates cerebral arterioles by activating smooth muscle cell plasma membrane KATP channels[J]. Am J Physiol Heart Circ Physiol.2011;300(6):H2088-2095.
[36]Guo Q, Jin S, Wang XL, Wang R, Xiao L, He RR, Wu YM. Hydrogen sulfide in the rostral ventrolateral medulla inhibits sympathetic vasomotor tone through ATP-sensitive K+ channels[J]. J Pharmacol Exp Ther.2011;338(2):458-465.
[37]Rosenegger D, Roth S, Lukowiak K. Learning and memory in Lymnaea are negatively altered by acute low-level concentrations of hydrogen sulphide. J Exp Biol. 2004;207(Pt 15):2621-2630.
[38]Qu K, Chen CP, Halliwell B, Moore PK, Wong PT.Hydrogen sulfide is a mediator of cerebral ischemic damage[J].Stroke,2006;37(3):889-893.
[39]Liu Y, Zou LP, Du JB, Wong V.Electro-acupuncture protects against hypoxic-ischemic brain-damaged immature rat via hydrogen sulfide as a possible mediator[J].Neurosci Lett.2010;485(1):74-78.
[40]任彩丽,赵红岗,蔡德亮,陈兰,毛智群,吴明,张健飞,龚雪阳,杨涛,黄长耀.脑梗死患者血浆中内源性硫化氢含量的变化[J].中国神经精神疾病杂志,2010,36(1)：43-45.
[41]Wong PT, Qu K, Chimon GN, Seah AB, Chang HM, Wong MC, Ng YK, Rumpel H, Halliwell B, Chen CP.High plasma Cyst(e) ine level may indicate poor clinical outcome in patients with acute st roke:po ssible invo lv ement of hydrogen sulfide[J]. J Neur opatho l Ex p Neur ol,2006,65(2):109-115.
[42]Chen X, Jhee KH, Kruger WD. Production of the neuromodulator H2S by cystathionine beta-synthase via the condensation of cysteine and homocysteine[J].J Biol Chem.2004;279(50):52082-52086.
[43]Kuhn W, Roebroek R, Blom H, van Oppenraaij D, Przuntek H, Kretschmer A, Buttner T, Woitalla D, Muller T. Elevated plasma levels of homocysteine in Parkinson's disease[J].Eur Neurol.1998;40(4):225-227.
[44]Muller T, Kuhn W. Cysteine elevation in levodopa-treated patients with Parkinson's disease[J].Mov Disord.2009;24(6):929-932.
[45]Hu LF, Lu M, Tiong CX, Dawe GS, Hu G, Bian JS.Neuroprotective effects of hydrogen sulfide on Parkinson's disease rat models [J].Aging Cell.2010;9(2):135-146.
[46]Lee M, Tazzari V, Giustarini D, Rossi R, Sparatore A, Del Soldato P, McGeer E, McGeer PL. Effects of hydrogen sulfide-releasing L-DOPA derivatives on glial activation:potential for treating Parkinson disease[J].J Biol Chem. 2010;285(23):17318-17328.
[47]Kida K, Yamada M, Tokuda K, Marutani E, Kakinohana M, Kaneki M, Ichinose F.Inhaled hydrogen sulfide prevents neurodegeneration and movement disorder in a mouse model of Parkinson's disease[J].Antioxid Redox Signal.2011;15(2):343-352.
[48]Eto K, Asada T, Arima K, Makifuchi T, Kimura H.Brain hydrogen sulfide is severely decreased in Alzheimer's disease[J]. Biochem Biophys Res Commun. 2002;293(5):1485-1488.
[49]Lee M, Schwab C, Yu S, McGeer E, McGeer PL. Astrocytes produce the antiinflammatory and neuroprotective agent hydrogen sulfide[J]. Neurobiol.Neurobiol Aging.2009;30(10):1523-1534.
[50]Belardinelli MC, Chabli A, Chadefaux-Vekemans B, Kamoun P. Urinary sulfur compounds in Down syndrome[J]. Clin Chem,2001,47(8):1500-1501.
[51]张国富,任彩丽,祁曙光,张云彪,陆志新,吕振雷.精神分裂症血浆硫化氢、同型半胱氨酸水平及其关系[J].中国神经精神疾病杂志,2010；36(8)：504-512.
[52]Skeberdis VA, Chevaleyre V, Lau CG, Goldberg JH, Pettit DL, Suadicani SO, Lin Y, Bennett MV, Yuste R, Castillo PE, Zukin RS. Protein kinase A regulates calcium permeability of NMD A receptors [J]. Nat. Neurosci.2011;15(2):343-352.
[53]Yang HW, Hu XD, Zhang HM, Xin WJ, Li MT, Zhang T, Zhou LJ, Liu XGRoles of CaMKII, PKA, and PKC in the induction and maintenance of LTP of C-fiber-evoked field potentials in rat spinal dorsal horn[J]. J. Neurophysiol. 2004;91(3):1122-1133.
[54]Lin F, Xin Y, Wang J, Ma L, Liu J, Liu C, Long L, Wang F, Jin Y, Zhou J, Chen J.Puerarin facilitates Ca(2+)-induced Ca(2+) release triggered by KC1 depolarization in primary cultured rat hippocampal neurons[J]. Eur. J. Pharmacol. Eur J Pharmacol. 2007;570(1-3):43-49.
[55]Hahn J, Jung W, Kim N, Uhm DY, Chung S. Characterization and regulation of rat microglial Ca(2+) release-activated Ca(2+) (CRAC) channel by protein kinases[J]. Glia.2000;31(2):118-124.
[56]Wu ML, Chen WH, Liu IH, Tseng CD, Wang SM. A novel effect of cyclic AMP on capacitative Ca2+ entry in cultured rat cerebellar astrocytes[J]. J Neurochem. 1999;73(3):1318-1328.
[57]Rossie S. Regulation of voltage-sensitive sodium and calcium channels by phosphorylation. Adv[J]. Second Messenger Phosphoprotein Res.1999;33,23-29.
[58]Schlessinger J. Cell signaling by receptor tyrosine kinases[J].Cell.2000; 103:211-216.
[59]Umemura K and Kimura H. Hydrogen sulfide enhances reducing activity in neurons:neurotrophic role of H2S in the brain[J]? Antioxid. Redox Signal. 2007;9:2035-2041
[60]Wong RW and Guillaud L. The role of epidermal growth factor and its receptors in mammalian CNS[J]. Cytokine Growth Factor Rev.2004;15:147-153.
[61]Roux PP and Blenis J. ERK and p38 MAPK-activated protein kinases:a family of protein kinases with diverse biological functions[J]. Microbiol. Mol. Biol. Rev. 2004;68:320-344.
[62]Hu LF, Wong PT, Moore PK, Bian JS. Hydrogen sulfide attenuates lipopolysaccharide-induced inflammation by inhibition of p38 mitogen-activated[J].J Neurochem.2007;100(4):1121-1128.
[63]Kyosseva SV. Mitogen-activated protein kinase signaling. Int. Rev[J]. Neurobiol. 2004;59:201-209.
[64]Yang G, Cao K, Wu L, Wang R. Cystathionine{gamma}-lyase overexpression inhibits cell proliferation via a H2S-dependent modulation of ERK 1/2 Phosphorylation andp21Cip/WAK-1.J Biol Chem[J].200419;279(47):49199-49205.
[65]Yang G, Sun X, Wang R. Hydrogen sulfide-induced apoptosis of human aorta smooth muscle cells via the activation of mitogen-activated protein kinases and caspase-3[J]. FASEB J.2004; 18(14):1782-1784.
[66]Hu LF, Pan TT, Neo KL, Yong QC, Bian JS.Cyclooxygenase-2 mediates the delayed cardioprotection induced by hydrogen sulfide preconditioning in isolated rat cardiomyocytes[J].Pflugers Arch.2008;455(6):971-978.
[67]Hydrogen sulfide induces the synthesis of proinflammatory cytokines in human monocyte cell line U937 via the ERK-NF-{kappa}B pathway[J]. J. Leukoc. Biol. 2007;81(5):1322-1332.
[68]Berridge MJ. Neuronal calcium signaling [J]. Neuron.1998;21:13-19.
[69]Clapham DE. Calcium signaling. Cell.2007; 131:1047-1053.
[70]Lynch MA. Long-term potentiation and memory[J]. Physiol. Rev.2004;84:87-93.
[71]Rizzuto R. Intracellular Ca(2+) pools in neuronal signalling [J]. Curr. Opin. Neurobiol.2001;11:306-312.
[72]Kombian SB, Reiffenstein RJ, Colmers WF. The actions of hydrogen sulfide on dorsal raphe serotonergic neurons in vitro[J].J Neurophysiol.1993;70(1):81-96.
[73]Lipscombe D, Helton TD, Xu W.L-type calcium channels:the low down[J]. J Neurophysiol.2004;92(5):2633-2641.
[74]Garcia-Bereguiain MA, Samhan-Arias AK, Martin-Romero FJ, Gutierrez-Merino C.Hydrogen sulfide raises cytosolic calcium in neurons through activation of L-type Ca2+ channels. Antioxid[J]. Redox Signal. Antioxid Redox Signal.2008;10(1):31-42.
[75]Nagai Y, Tsugane M, Oka J, Kimura H.Hydrogen sulfide induces calcium waves in astrocytes[J]. FASEB J.2004;18(3):557-559.
[76]Huguenard JR. Low-threshold calcium currents in central nervous system neurons[J]. Annu. Rev. Physiol.1996;58:329-333.
[77]Huguenard JR. Low-voltage-activated (T-type) calcium-channel genes identified[J].Trends Neurosci.1998;21:451-457.
[78]Kawabata A, Ishiki T, Nagasawa K, Yoshida S, Maeda Y, Takahashi T, Sekiguchi F, Wada T, Ichida S, Nishikawa H. Hydrogen sulfide as a novel nociceptive messenger [J]. Pain.2007; 132(1-2):74-81.
[79]Maeda Y, Aoki Y, Sekiguchi F, Matsunami M, Takahashi T, Nishikawa H, Kawabata A.Hyperalgesia induced by spinal and peripheral hydrogen sulfide:evidence for involvement of Cav3.2 T-type calcium channels[J]. Pain.2009;142(1-2):127-132.
[80]Nagasawa K, Tarui T, Yoshida S, Sekiguchi F, Matsunami M, Ohi A, Fukami K, Ichida S, Nishikawa H, Kawabata A.Hydrogen sulfide evokes neurite outgrowth and expression of high-voltage-activated Ca2+ currents in NG108-15 cells:involvement of T-type Ca2+ channels[J]. J Neurochem.2009;108(3):676-684.
[81]Scemes E and Giaume C. Astrocyte calcium waves:what they are and what they do[J]. Glia.2006;54:716-721.
[82]Perea G and Araque A. Glial calcium signaling and neuron-glia communication[J]. Cell Calcium.2005;38:375-382.
[83]Farber K and Kettenmann H. Functional role of calcium signals for microglial function[J]. Glia.2006;54:656-661.
[84]Rizzuto R. Intracellular Ca(2+) pools in neuronal signalling [J]. Curr. Opin. Neurobiol.2001;11:306-312.
[85]Hidalgo C. Cross talk between Ca2+ and redox signalling cascades in muscle and neurons through the combined activation of ryanodine receptors/Ca2+ release channels. Philos[J]. Trans. R. Soc. Lond. B:Biol. Sci.2005;360:2237-2243.
[86]Verkhratsky A. The endoplasmic reticulum and neuronal calcium signalling [J]. Cell Calcium,2002; 32:393-398.
[87]Dawe GS, Han SP, Bian JS, Moore PK. Hydrogen sulphide in the hypothalamus causes an ATP-sensitive K+ channel-dependent decrease in blood pressure in freely moving rats[J]. Neuroscience.2008; 152:169-177.
[88]Kombian SB, Reiffenstein RJ, Colmers WF.The actions of hydrogen sulfide on dorsal raphe serotonergic neurons in vitro[J]. J. Neurophysiol.1993;70(1):81-96.
[89]Kimura Y, Dargusch R, Schubert D, Kimura H.Hydrogen sulfide protects HT22 neuronal cells from oxidative stress[J].. Antioxid. Redox Signal 2006;8(3-4):661-670.
[90]Lee SW, Cheng Y, Moore PK, Bian JS.Hydrogen sulphide regulates intracellular pH in vascular smooth muscle cells[J].Biochem.Biophys.Res.Commun. 2007;358(4):1142-1147.
[91]Kaila K. Ionic basis of GABAA receptor channel function in the nervous system[J]. Prog. Neurobiol.1994; 42:489-496.
[92]Chebib M, Johnston GA. The'ABC of GAB A receptors:a brief review [J]. Clin. Exp. Pharmacol. Physiol.1999.26:937-943.
[93]Han Y, Qin J, Chang X, Yang Z, Tang X, Du J.Hydrogen sulfide may improve the hippocampal damage induced by recurrent febrile seizures in rats[J]. Biochem. Biophys. Res. Commun.2005;327(2):431-436.
[94]Bading H, Ginty DD, Greenberg ME. Regulation of gene expression in hippocampal neurons by distinct calcium signaling pathways[J]. Science.1993;260:181-186.
[95]Pietrobon D. Calcium channels and channelopathies of the central nervous system[J]. Mol. Neurobiol.2002;25:31-38
[96]Weisskopf MG, Bauer EP, LeDoux JE.L-type voltage-gated calcium channels mediate NMDA-independent associative long-term potentiation at thalamic input synapses to the amygdala[J]. J. Neurosci.1999;19(23):10512-10519.
[97]Hudspith MJ. Glutamate:a role in normal brain function, anaesthesia,analgesia and CNS injury[J]. Br. J. Anaesth 1997,78:731-736.
[98]Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R. Glutamate receptor ion channels: structure, regulation, and function[J].Pharmacol Rev.2010;62(3):405-496.
[99]Gagliardi RJ. Neuroprotection, excitotoxicity and NMD A antagonists [J].. Arq.Neuropsiquiatr 2000; 58:583-591.
[100]Dingledine R, Borges K, Bowie D, Traynelis SF.The glutamate receptor ion channels[J]. Pharmacol Rev.1999;51(1):7-61.
[101]Cheung NS, Peng ZF, Chen MJ, Moore PK, Whiteman M.Hydrogen sulfide induced neuronal death occurs via glutamate receptor and is associated with calpain activation and lysosomal rupture in mouse primary cortical neurons[J].. Neuropharmacology 2007;53(4):505-514.
[102]Erecinska M and Silver I A. Metabolism and role of glutamate in mammalian brain[J]. Prog. Neurobiol.1990;35:245-250.
[103]Hu LF,Lu M,Wu ZY,Wong PT,Bian JS.Hydrogen sulfide inhibits rotenone-induced apoptosis via preservation of mitochondrial function[J]. Mol.Pharmacol. 2009;75(1):27-34.